C57BL/6-Crbn^tm2.1Ble/J

Stock number: 035831
Product name: Crbn^V380E/I391V
Research areas: Cancer Research, Hematological Research, Immunology, Inflammation and Autoimmunity Research, Research Tools

Description

Crbn^V380E/I391V mice carry both V380E and I391V changes in the mouse Crbn (cereblon) gene, providing an in vivo model for studying the effects of a newer thalidomide analogues and are suitable for use in applications related to the study of haematological malignancy, thalidomide analogue treatment, and treatment-induced cytopenias and teratogenicity.

Detailed description

Mice carrying the wildtype cereblon (Crbn) gene are intrinsically resistant to thalidomide and related analogue drugs. These drugs act by inducing protein substrate degradation and are widely used in the treatment of human disease, most notably the haematological malignancy multiple myeloma.

A previous mouse strain humanized at Crbn I391V (see Stock No. 032487) shows in vivo sensitivity to the thalidomide analogue Lenalidomide. However newer analogues that degrade an increased substrate repertoire, e.g. the tool compound CC-885 that degrades G1 To S Phase Transition 1 (GSPT1) protein, require the V380E humanization. Furthermore, some drugs/substrates require both the I391V and V380E changes for any/optimal substrate degradation.

These Crbn^V380E/I391V mice carry both V380E and I391V changes in the mouse Crbn gene, providing an in vivo model for studying the effects of a newer thalidomide analogues and a more accurate representation of protein substrate degradation to inform studies of treatment effects, response, and resistance. They are suitable for use in applications related to the study of haematological malignancy, thalidomide analogue treatment, and treatment-induced cytopenias and teratogenicity.

Development

V380E (GTG to GAG; exon 10) and I391V (ATT to GTG; exon 11) mutations were introduced to the mouse Crbn gene via homologous recombination in iTL BF1 C57BL/6 FLP-derived embryonic stem (ES) cells. A loxP/FRT-flanked neomycin cassette placed in intron 9 was excised in the ES cells expressing FLP recombinase, leaving one set of loxP/FRT sites.

Upon arrival at The Jackson Laboratory, sperm was cryopreserved. Cryorecovery/live colony development will involve C57BL/6J (Stock No. 000664).

In 2022, a 48 SNP (single nucleotide polymorphism) panel analysis, with 43 markers covering all 19 chromosomes and the X chromosome, as well as 5 markers that distinguish between the C57BL/6J and C57BL/6N substrains, was performed on the males sent to The Jackson Laboratory Repository. Three of the 5 markers that determine C57BL/6J from C57BL/6N were found to be segregating, including the rd8 recessive mutation associated with retinal degeneration on Chromosome 1 within the Crb1 locus. These data suggest the mice sent to The Jackson Laboratory Repository were on a mixed C57BL/6N;C57BL/6J genetic background.

Allele

Symbol: Crbn^tm2.1Ble
Name: targeted mutation 2.1, Benjamin L Ebert
MGI accession ID: MGI:7312145
Generation method: Targeted
Attributes: Humanized sequence
Synonyms: Crbn^V380E/I391V
Marker symbol: Crbn
Marker name: cereblon
Marker synonyms: 2610203G15Rik; 2900045O07Rik; MRT2; MRT2A
Chromosome: 6
Strain of origin: C57BL/6NTac
Molecular note: V380E (GTG to GAG; exon 10) and I391V (ATT to GTG; exon 11) mutations were introduced to the gene via homologous recombination. A loxP/FRT-flanked neomycin cassette placed in intron 9 was excised in the ES cells expressing FLP recombinase, leaving one set of loxP/FRT sites. The humanized mutations create sensitivity to thalidomide analogues in the mouse.